H1 histones control the epigenetic landscape by local chromatin compaction.
| Title: | H1 histones control the epigenetic landscape by local chromatin compaction. |
|---|---|
| Authors: | Willcockson MA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Healton SE; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Weiss CN; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Bartholdy BA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Botbol Y; Department of Pathology, Albert Einstein College of Medicine, New York, NY, USA.; Mishra LN; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Sidhwani DS; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Wilson TJ; Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA.; Pinto HB; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Maron MI; Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA.; Skalina KA; Department of Pathology, Albert Einstein College of Medicine, New York, NY, USA.; Toro LN; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.; Zhao J; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Lee CH; Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA.; Howard Hughes Medical Institute, Chevy Chase, MD, USA.; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.; Hou H; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Yusufova N; Cell & Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY, USA.; Division of Hematology/Oncology, Department of Medicine, Biochemistry, Weill Cornell Medicine, New York, NY, USA.; Meydan C; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.; Osunsade A; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA.; David Y; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA.; Cesarman E; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.; Melnick AM; Division of Hematology/Oncology, Department of Medicine, Biochemistry, Weill Cornell Medicine, New York, NY, USA.; Sidoli S; Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, PA, USA.; Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA.; Garcia BA; Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, PA, USA.; Edelmann W; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.; Macian F; Department of Pathology, Albert Einstein College of Medicine, New York, NY, USA.; Skoultchi AI; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA. arthur.skoultchi@einsteinmed.org. |
| Source: | Nature [Nature] 2021 Jan; Vol. 589 (7841), pp. 293-298. Date of Electronic Publication: 2020 Dec 09. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| Imprint Name(s): | Publication: Basingstoke : Nature Publishing Group; Original Publication: London, Macmillan Journals ltd. |
| MeSH Terms: | Chromatin Assembly and Disassembly* ; Epigenesis, Genetic*; Chromatin/*genetics ; Histones/*metabolism; CD8-Positive T-Lymphocytes/metabolism ; Cell Differentiation/genetics ; Chromatin/chemistry ; Chromatin/metabolism ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Histones/chemistry ; Lymphocyte Activation/genetics ; Animals ; Female ; Gene Silencing ; Male ; Methylation ; Mice ; Mice, Knockout |
| Abstract: | H1 linker histones are the most abundant chromatin-binding proteins1. In vitro studies indicate that their association with chromatin determines nucleosome spacing and enables arrays of nucleosomes to fold into more compact chromatin structures. However, the in vivo roles of H1 are poorly understood2. Here we show that the local density of H1 controls the balance of repressive and active chromatin domains by promoting genomic compaction. We generated a conditional triple-H1-knockout mouse strain and depleted H1 in haematopoietic cells. H1 depletion in T cells leads to de-repression of T cell activation genes, a process that mimics normal T cell activation. Comparison of chromatin structure in normal and H1-depleted CD8+ T cells reveals that H1-mediated chromatin compaction occurs primarily in regions of the genome containing higher than average levels of H1: the chromosome conformation capture (Hi-C) B compartment and regions of the Hi-C A compartment marked by PRC2. Reduction of H1 stoichiometry leads to decreased H3K27 methylation, increased H3K36 methylation, B-to-A-compartment shifting and an increase in interaction frequency between compartments. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. Our results establish H1 as a critical regulator of gene silencing through localized control of chromatin compaction, 3D genome organization and the epigenetic landscape. |
| Comments: | Comment in: Nat Rev Genet. 2021 Feb;22(2):68-69. doi: 10.1038/s41576-020-00323-7.. (PMID: 33323999) |
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| Grant Information: | GM110104 United States NH NIH HHS; AI118891 United States NH NIH HHS; P01 CA196539 United States CA NCI NIH HHS; R01 CA234561 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; R01 AI118891 United States AI NIAID NIH HHS; F30 DK107182 United States DK NIDDK NIH HHS; T32 GM007288 United States GM NIGMS NIH HHS; R01 CA226861 United States CA NCI NIH HHS; P30 CA013330 United States CA NCI NIH HHS; R01 GM147165 United States GM NIGMS NIH HHS; R01 GM116143 United States GM NIGMS NIH HHS; F30 CA210539 United States CA NCI NIH HHS; R35 GM138386 United States GM NIGMS NIH HHS; F30 DK108532 United States DK NIDDK NIH HHS |
| Substance Nomenclature: | 0 (Chromatin); 0 (Histones); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 2.1.1.43 (Ezh2 protein, mouse) |
| Entry Date(s): | Date Created: 20201210 Date Completed: 20210225 Latest Revision: 20260306 |
| Update Code: | 20260306 |
| PubMed Central ID: | PMC8110206 |
| DOI: | 10.1038/s41586-020-3032-z |
| PMID: | 33299182 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't